title: JNK inhibitor SP600125 enhances TGF-β-induced apoptosis of RBE human cholangiocarcinoma cells in a Smad-dependent manner.
abstract: Transforming growth factor β (TGF-β) signaling is pivotal for the progression of specific types of tumors at certain stages. However, the mechanism by which TGF-β is regulated by other factors remains unclear. In this study, the involvement of SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), in TGF-β-induced apoptosis of the RBE human cholangiocarcinoma cell line was investigated. Exogenous TGF-β1 activated Smad and non‑Smad signaling pathways, including the JNK pathway in RBE cells, and induced apoptosis, which was inhibited by knockdown of Smad4 expression. SP600125 increased the TGF-β1‑induced phosphorylation of Smad2 and Smad3, which enhanced the TGF-β1‑induced transcriptional response and apoptosis in RBE cells. The effect of SP600125 on the transcriptional response and apoptosis was reduced by knockdown of Smad4 expression. In addition, TGF-β1‑induced apoptosis was abrogated using the pan-caspase inhibitor Z‑VAD-fmk. SP600125 promoted the TGF-β1‑induced caspase cleavage, while knockdown of Smad4 expression counteracted this effect. These results indicate that SP600125 enhances TGF-β-induced apoptosis of RBE cells through a Smad‑dependent pathway that involves Smad‑dependent caspase activation. SP600125 is hypothesized to be an ideal therapeutic candidate for treating human cholangiocarcinoma.
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Lin
authors.forename: Binhao
authors.initials: B
authors.lastname: Zhang
authors.forename: Huifang
authors.initials: H
authors.lastname: Liang
authors.forename: Yulei
authors.initials: Y
authors.lastname: Lu
authors.forename: Xi
authors.initials: X
authors.lastname: Ai
authors.forename: Bixiang
authors.initials: B
authors.lastname: Zhang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
mesh_terms: D000873:Anthracenes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D000873:Anthracenes; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: SP600125; transforming  growth  factor  β; apoptosis; Smad; cholangiocarcinoma